Growth hormone (GH) is well recognized as an important regulator of body growth and metabolism. It is currently used to treat children of short stature, growth hormone deficient adults, surgical patients (to prevent muscle wasting), and burn patients (increase growth rate of skin), to name a few of its therapeutic uses. Other cytokines, hormones and growth factors that act by a similar mechanism regulate a whole host of important body functions, including milk production, the immune system, nerve growth and regeneration, appetite and body fat composition.
As the therapeutic potential of GH (and GH suppression) becomes apparent, a more mechanistic understanding of GH action at the cellular and molecular levels is needed. The initial steps in the pathway following the binding of GH to its receptor have recently been established. It is now known that growth hormone receptor (GHR) forms a complex with a tyrosine kinase. See Argetsinger et al., "Identification of JAK2 as a Growth Hormone Receptor-Associated Tyrosine Kinase," Cell 74:237 (1993). The kinase, termed JAK2, is a member of the Janus family of tyrosine kinases. In addition to having a kinase domain, these proteins are characterized by the presence of a second kinase-like domain and the absence of Src homology 2 (SH2), SH3, and membrane-spanning domains. Ligand binding to the cytokine receptor appears to activate the kinase, causing tyrosyl phosphorylation of both JAK2 and the receptor involved, such as GHR for GH mediated signaling. The steps beyond this point are largely unclear, although it has been presumed that other intracellular proteins are recruited to JAK2-receptor complexes.
It is important that the other members of the pathway be identified, given that direct use of some growth factors, such as GH is associated with undesirable side-effects. A better understanding of the signaling pathway and elucidation of the cellular mechanisms by which these agents act is required, in order to define the origin of diseases caused by their malfunction as well as design specific therapeutics.